Pharmaceutical tablets in divisible form containing an indentation known as a score have long been known and widely used. Problems with breaking scored tablets are well-known. These problems include loss of active drug and inaccurate division of the tablet, so that a tablet intended to be divided into two equal half-tablets often does not come close to that ideal.
Many drugs require dosage adjustments, such as warfarin, the scored tablets of which are frequently broken. These dosage adjustments through tablet breaking by patients have been determined to be imprecise. As the following discussion demonstrates, for many years experts have called upon the pharmaceutical industry to improve the quality of tablet breaking, yet such has not been optimized until the current invention.
In 1984, Stimpel et al. (“Stimpel”), described the relative accuracy of breaking of various tablets for treatment of cardiovascular problems. M. Stimpel et al., “Breaking Tablets in Half.” The Lancet (1984):1299. Even though breaking was performed by a sophisticated, dexterous person, Stimpel found that breaking was not accurate, and opined that real world use by patients would provide yet more unsatisfactory results. Stimpel called upon the pharmaceutical industry to improve the accuracy of splitting tablets: “Clearly any assumption that halving a tablet will not lead to inaccurate doses is invalid. This potential source of inaccuracy could be even more significant in clinical situations (our study was done under ideal conditions) and the pharmaceutical industry should tackle it, either by improving divisibility (as already has been done for lopressor and logroton) or, even better, by marketing a wider range of unscored tablets to provide all the doses that might be indicated clinically.”
Despite that finding and statement, and despite the issuance of various patents relating to optimizing a scoring pattern and/or tablet shape, Rodenhuis et al., (2004) noted that: “Improving the functioning of score lines may be a more practical approach than banning this dosage form” (emphasis added). N. Rodenhuis et al., “The rationale of scored tablets as dosage form.” European J. of Pharmaceutical Sciences 21 (2004):305-308 (hereafter “Rodenhuis”). Rodenhuis observed that European regulatory authorities started a policy to discourage scoring of tablets in 1998. This policy change, according to Rodenhuis, likely related to “many recent reports of bad functioning score lines” that “many scored tablets are difficult to break,” and that “many scored tablets show unsatisfactory mass uniformity of the subdivided halves.” The authors then go on to describe useful aspects of scoring tablets. For a comprehensive review article on this topic, see van Santen, E., Barends, D. M. and Frijlink, H. W. “Breaking of scored tablets: a review.” European J. of Pharmaceutics and Biopharmaceutics 53 (2002):139-145.
Some current studies that demonstrate the severity of the problem are described below.
Peek et al., (2002), studied tablet splitting by “elderly patients” aged 50-79. Peek, B. T., Al-Achi, A., and Coombs, S. J. “Accuracy of Tablet Splitting by Elderly Patients.” The Journal of the American Medical Association 288 No. 4 (2002):139-145. Breaking scored tablets with mechanical tablet splitters without specific instruction led to highly unsatisfactory separating of the tablets. For example, warfarin 5 mg was on average split into 1.9 and 3.1 mg tablets. This potent anticoagulant has such a narrow therapeutic range that 2, 2.5, and 3 mg tablet doses are manufactured. Biron et al., (1999), demonstrated that warfarin 10 mg also often split to less than 4.25 or greater than 5.75 mg. Biron, C., Liczner, P., Hansel, S. and Schved, J. F., “Oral Anticoagulant Drugs: Do Not Cut Tablets in Quarters.” Thromb Haemost 1201 (1999). In addition, they demonstrated that loss of mass due to crumbling or chipping from the breaking of the warfarin tablets was statistically significant. They also demonstrated that quartering of the tablets was grossly inaccurate.
McDevitt et al., (1998), found that 25 mg unscored hydrochlorothiazide tablets were manually split badly enough that 12.4% deviated by more than 20% from ideal weight. McDevitt, J. T., Gurst, A. H. and Chen, Y. “Accuracy of Tablet Splitting.” Pharmacotherapy 18 No. 1 (1998):193-197. 77% of the test subjects stated that they would be willing to pay a premium for individually produced 12.5 mg tablets rather than split 25 mg unscored tablets.
Rosenberg et al., (2002), studied pharmacist-dispensed split tablets. Rosenberg, J. M., Nathan, J. P. and Plakogiannis, F. “Weight Variability of Pharmacist-Dispensed Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):200-205. They found that “tablet splitting resulted in an unacceptably high incidence of weight variation.” They recommended that “standards should be developed to ensure uniformity of split tablets.”
Teng et al., (2002), using a trained individual in a laboratory setting to split tablets, concluded that “the majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP (United States Pharmacopeia) uniformity test . . . . The practice of dividing tablets to save costs or to improve a dosage regimen . . . is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.” Teng, J., Song, C. K., Williams, R. L. and Polli, J. E. “Lack of Medication Dose Uniformity in Commonly Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):195-199.
Rodenhuis reported that 31% of all tablets in one Netherlands study were subdivided before being swallowed. In the U.S., “managed care” insurance organizations may encourage splitting by patients of unscored tablets that may not even have symmetrical shapes. Many drug products in the US either are unscored tablets, or are provided as capsules despite being able to be produced as tablets.
The invention is directed to amelioration of the problems described above.
In addition, treatment with combination products is common in pharmaceuticals, meaning that one dosage form may contain more than one active ingredient. This means of treatment may in part be discussed as follows:
A relevant field to the invention is the field of combination drug therapy for systemic arterial hypertension (“hypertension”). Technically, combination therapy for hypertension involves the use of two or more drugs on a regular basis to treat a patient's hypertension. Generally, this term implies daily treatment with at least two drug products.
Combination therapy has long been used to treat hypertension. It is widely estimated that approximately half of all cases of hypertension cannot be treated to goal blood pressure with one drug at a maximally tolerated dosage. To aid in treatment, solid oral dosage forms have been produced that contain a plurality of active agents within one tablet or capsule. These dosage forms are known as “fixed-dose” combination products, because a patient or pharmacist has no means of separating one active agent from another. Sica, D., Drugs, 2002; 62 (3): “Rationale for Fixed-Dose Combinations in the Treatment of Hypertension,” states that “a considerable legacy, dating to the 1950's, exists for fixed-dose combination therapies.” Later in the same article, the author pinpoints a deficiency with the fixed-dose approach, which embodiments of the current invention largely correct: “A disadvantage to the use of fixed-dose combination is a lack of dose administration flexibility for its individual components, although it is uncommon for physicians to maximally exploit the dose administration flexibility inherent to the use of free combinations. With fixed-dose combination therapy, if conditional amounts of either drug are required for BP control, a separate prescription will be required. This increases complexity of the regimen and has the potential to negatively affect compliance. In addition, fixed-dose combination therapy may not provide adequate drug amounts to manage illnesses, such as angina or congestive heart failure, which commonly co-exist with hypertension.”
The invention provides a means to improve the above situation, by allowing flexibility of dosing within a combination dosage form.
The current invention describes a tablet shape adapted for separating one vertically disposed segment from another. In the large field of immediate release pharmaceuticals, the relative dimensions of the tablet are novel. Commercially, the only product that as produced is taller than it is wide is Concerta®, which is a three-segment tablet, two of which segments are devoted to controlled release of the active drug, methylphenidate. Concerta utilizes the OROS® system, which utilizes the taller-than-wide geometry as part of its controlled release characteristics. The manufacturer's directions for the use of Concerta specify that the tablets should never be broken.
Except for Concerta, tablets, including those involving layers vertically disposed one on the other, have been produced wider than they are tall.
A tablet press manufacturer, Korsch AG of Germany, has developed a tablet press that can produce up to five vertically disposed layers. It has been utilized to produce taller-than-wide five-layer tablets having no active drugs therein and has also been used to manufacture Concerta.